The invention is directed to certain substituted benzamide compounds that are useful as inhibitors of picornaviruses such as human rhinoviruses (HRV). The invention is also directed to pharmaceutical compositions containing such compounds, as well as methods of treating HRV infection or the common cold by administering effective amounts of such compounds.
HRVs, which are the primary cause of the common cold in man, belong to the picornavirus family. (Couch, R. B. Rhinoviruses. In Virology; Fields, B. N., Knipe, D. M., Eds.; Raven Press: New York, 1990; Volume 1, Chapter 22, pp 607-629; See McKinlay, M. A.; Pevear, D. C.; Rossman, M. G. Treatment of the Picornavirus Common Cold by Inhibitors of Viral Uncoating and Attachment. Annu. Rev. Microbiol. 1992, 46, 635-654, and references cited therein; Phillpotts, R. J., Tyrell, D. A. J. Rhinovirus Colds. Br. Med. Bull. 1985, 41, 386-390; Gwaltney, J. M. Rhinoviruses. In Viral Infections of Humans, Evans, A. S., Ed.; Plunem Publishing Corp.: New York, 1982; Chapter 20, pp 491-517; Gwaltney, J. M. The Common Cold. In Principles and Practices of Infectious Diseases, Mandell, G. L., Douglas, R. G., Bennett, J. E., Eds.; John Wiley and Sons: New York, 1985; Chapter 38, pp 351-355.) Picornaviruses, such as HRV, have a single positive-stranded RNA genome, (See Krxc3xa4usslich, H. -G., Wimmer, E. Viral Proteinases. Annu. Rev. Biochem. 1988, 57, 701-754, and references cited therein; Callahan, P. L.; Mizutani, S.; Colonno, R. J. Molecular Cloning and Complete Sequence Determination of the RNA Genome of Human Rhinovirus Type 14. Proc. Natl. Acad. Sci. USA 1985, 82, 732-736; Stanway, G., Hughes, P. J., Mountford, R. C.; Minor, P. D., Almond, J. W. The complete nucleotide sequence of the common cold virus: human rhinovirus 14. Nucleic Acids Res. 1984, 12, 7859-7875; Lee, W. -M., Wang, W., Rueckart, R. R. Complete sequence of the RNA genome of human rhinovirus 16, a clinically useful common cold virus belonging to the ICAM-1 receptor group. Virus Genes 1995, 9, 177-181.), which is translated into a polyprotein of over 2000 amino acids. The 2A and 3C protease (3CP) process this polyprotein into its functional viral proteins in HRV. (Orr, D. C., Long, A. C., Kay, J., Dunn, B. M., Cameron, J. M. Hydrolysis of a Series of Synthetic Peptide Substrates by the Human Rhinovirus 14 3C Protease, Cloned and Express in Escherichia coli. J. Gen. Virol. 1989, 70, 2931-2942. Cordingly, M. G.; Register, R. B.; Callahan, P. L., Garsky, V. M., Colonno, R. J. Cleavage of Small Peptides In Vitro by Human Rhinovirus 14 3C Protease Expressed in Escherichia coli. J. Virol. 1989, 63, 5037-5045.) The consensus cleavage site for the 3CP in the viral polyprotein is between glutamine (P1) and glycine (P1xe2x80x2) residues. While the 3CP is a cysteine protease, its tertiary structure is reminiscent of trypsin-like serine proteases. (Matthews, D. A., Smith, W. A., Ferre, R. A., Condon, B., Budahazi, G., Sisson, W., Villafranca, J. E., Janson, C. A., McElroy, H. E., Gribskov, C. L., Worland, S. Structure of Human Rhinovirus 3C Protease Reveals a Trypsin-like Polypeptide Fold, RNA-Binding Site, and Means for Cleaving Precursor Polyprotein. Cell 1994, 77, 761-771. Bazan, J. F., Fletterick, R. J. Viral Cysteine Proteases are Homologous to the Trypsin-like Family of Serine Proteases: Structural and Functional Implications. Proc. Natl. Acad. Sci. USA 1988, 85, 7872-7876; Gorbalenya, A. E., Blinov, V. M., Donchenko, A. P. Poliovirus-encoded Proteinase 3C: A Possible Evolutionary Link Between Cellular Serine and Cysteine Proteinase Families. FEBS Lett. 1986, 194, 253-257; Allaire, M., Chernala, M. M., Malcolm, B. A., James, M. N. G. Picornaviral 3C cysteine proteinases have a fold similar to chymotrypsin-like serine proteinases. Nature 1994, 369, 72-76.) The requirement for proteolytic processing of the viral polyprotein, supported by mutagenesis of the active site residues, (Ivanoff, L. A., Towatari, T., Ray, J., Korant, B. D., Petteway, S. R., Jr. Proc. Nat. Acad. Sci. U.S.A. 1986 83, 5392-5396; Hammerle, T., Hellen, C. U. T., Wimmer, E. J. Biol. Chem. 1991 266 5412-541; Kean, K. M., Teterina, N. L., Marc, D., Girard, M. Virology 1991 181 609-619) makes the 3CP a viable target for antirhinoviral therapy.
Solution of the HRV 3CP crystal structure has facilitated the design of a number of 3CP inhibitors, which have been previously reported (Webber, S. E., Tikhe, J., Worland, S. T., Fuhrman, S. A., Hendrickson, T. F., Matthews, D. A., Love, R. A., Patick, A. K., Meador, J. W., Ferre, R. A., Brown, E. L., DeLisle, D. M., Ford, C. E., Binford, S. L. Design, Synthesis, and Evaluation of Nonpeptidic Inhibitors of Human Rhinovirus 3C Protease. J. Med. Chem. 1996, 39, 5072-5082; Webber, S. E., Okano, K., Little, T., Reich, S. H., Xin, Y., Fuhrman, S. A., Matthews, D. A., Love, R. A., Hendrickson, T. F., Patick, A. K., Meador, J. W., Ferre, R. A., Brown, E. L., Ford, C. E., Binford, S. L., Worland, S. T. Tripeptide Aldehyde Inhibitors of Human Rhinovirus 3C Protease: Design, Synthesis, Biological Evaluation, and Cocrystal Structure Solution of P1 Glutamine Isosteric Replacements J. Med. Chem. 1998, 41, 2786-2805; Dragovich, P. S., Webber, S. E, Babine, R. E., Fuhrman, S. A., Patick, A. K., Matthews, D. A., Lee, C. A., Reich, S. H., Prins, T. J., Marakovits, J. T., Littlefield, E. S., Zhou, R., Tikhe, J., Ford, C. E., Wallace, M. B., Meador, III, J. W., Ferre, R., Brown, E. L., Binford, S. L., Harr, J.E. V., DeLisle, D. M. and Worland, S. T. Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 1. Michael Acceptor Structure-Activity Studies J. Med. Chem. 1998,41, 2806; Dragovich, P. S., Webber, S. E, Babine, R. E., Fuhrman, S. A., Patick, A. K., Matthews, D. A., Reich, S. H., Marakovits, J. T., Prins, T. J., Zhou, R., Tikhe, J., Littlefield, E. S., Bleckman, T. M., Wallace, M. W., Little, T. L., Ford, C. E., Wallace, M. B., Meador, III, J. W., Ferre, R., Brown, E. L., Binford, S. L, DeLisle, D. M. and Worland, S. T. Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 2. Peptide Structure-Activity Studies. J. Med. Chem. 1998, 41, 2819; Kaldor, S. W., Hammond, M., Dressman, B. A., Labus, J. M., Chadwell, F. W., Kline, A. D., Heinz, B. A. Glutamine-derived Aldehydes for the Inhibition of Human Rhinovirus 3C Protease. Bioorg. Med. Chem. Lett. 1995, 5, 2021-2026; Shepherd, T. A., Cox, G. A., McKinney, E., Tang, J., Wakulchik, M., Zimmerman, R. E., Villarreal, E. C. Small Peptidic Aldehyde Inhibitors of Human Rhinovirus 3C Protease. Bioorg. Med. Chem. Lett. 1996, 6, 2893-2896; Malcolm, B. A., Lowe, C., Shechosky, S., McKay, R. T., Yang, C. C., Shah, V. J., Simon, R. J., Vederas, J. C., Santi, D. V. Peptide Aldehyde Inhibitors of Hepatitis A Virus 3C Proteinase. Biochem. 1995, 34, 8172-8179. Sham, H. L., Rosenbrook, W., Kati, W., Betebenner, D. A., Wideburg, N. E., Saldivar, A., Plattner, J. J., Norbeck, D. W. Potent inhibitor of the human rhinovirus (HRV) 3C protease containing a backbone modified glutamine. J. Chem. Soc. Perkin Trans. 1 1995, 1081-1082; Brill, G. M., Kati, W. M., Montgomery, D., Karwowski, J. P., Humphrey, P. E., Jackson, M., Clement J. J., Kadam, S., Chen, R. H., McAlpine, J. B. Novel Triterpene Sulfates from Fusarium compactum Using a Rhinovirus 3C Protease Inhibitor Screen. J. Antibiotics 1996, 49, 541-546; Skiles, J. W., McNeil, D. Spiro Indolinone Beta-lactams, Inhibitors of Poliovirus and Rhinovirus 3C-Proteinases. Tetrahedron Lett. 1990, 31, 7277-7280; Kadam, S., Poddig, J., Humphrey, P., Karwowski, J., Jackson, M., Tennent, S., Fung, L., Hochlowski, J., Rasmussen, R., McAlpine, J. Citrinin Hydrate and Radicinin: Human Rhinovirus 3C-Protease Inhibitors Discovered in a Target-directed Microbial Screen. J. Antibiotics 1994, 47, 836-839; Singh, S. B., Cordingley, M. G., Ball, R. G., Smith, J. L., Dombrowski, A. W., Goetz, M. A. Structure and Stereochemistry of Thysanone: A Novel Human Rhinovirus 3C-Protease Inhibitor from Thysanophora penicilloides. Tetrahedron Lett. 1991, 32, 5279-5282; Jungheim, L. N., Cohen, J. D., Johnson, R. B., Villarreal, E. C., Wakulchik, M., Loncharich, R. J., Wang, Q. M. Inhibition of Human Rhinovirus 3C Protease by Homophthalimides. Bioorg. Med. Chem. Lett. 1997, 7, 1589-1594; Kong, J., Venkatraman, S., Furness, K., Nimkar, S., Shepard, T., Wang, Q., Aube"", J., Hanzlik, R. P. Synthesis and Evaluation of Peptidyl Michael Acceptors That Inactivate Human Rhinovirus 3C Protease and Inhibit Virus Replication J. Med. Chem. 1998 41 2579-2587.) There is still a desire, however, to discover nonpeptide, low molecular weight inhibitor of 3CP with potent antirhinoviral activity.
Accordingly, an object of the invention is to discover small-molecule, nonpeptide inhibitors of HRV 3CP (RVP). An additional object is to discover irreversible inhibitors of RVP that are orally available.
Other objects and advantages of the invention, which will become apparent from the detailed description that follows, have been achieved through the discovery of benzamide-containing compounds such as those of the following general formula: 
wherein:
R10, R20, and R30 are each independently hydrogen, hydroxy, or halogen, or an unsubstituted or substituted alkyl, O-alkyl, aryl, O-aryl, heteroaryl, O-heteroaryl, alkoxy, aryloxy, or heteroaryloxy group;
R40 is hydrogen or an unsubstituted or substituted alkyl or aryl group; and
R is an unsubstituted or substituted alkyl, aryl, heteroaryl, O-alkyl, O-aryl, or O-heteroaryl group.
Such compounds, as well as their pharmaceutically acceptable salts, solvates, prodrugs, and pharmaceutically active metabolites, are useful agents for pharmaceutical indications mediated by inhibition of RVP, such as for cold treatments.